ABSTRACT
The LEAN manufacturing and management model, developed from the Toyota Production System (TPS), has triggered major transformations
in various manufacturing industries. Implementation in the field of biopharmaceuticals, however, has been limited to date.
We believe that properly implementing LEAN in biopharmaceutical manufacturing can bring huge benefits, despite the complexity
of biotechnology and the stringent regulatory requirements. In this article, we provide practical examples to highlight the
areas where such benefits can be achieved. We also describe our qualification concept and the implementation of a new flat
and crossfunctional process-oriented organization in manufacturing sites, in line with TPS principles, to ensure the development
of a "LEAN" culture—a culture of continuous improvement.
Hermann Horvath/Novartis AG
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LEAN can be defined as a manufacturing and management model that aims to reduce the time from customer order to delivery by
eliminating sources of waste and by making the product flow through value-adding steps without interruption. It is derived
from the Toyota Production System (TPS), which Toyota started developing in the 1950s. TPS has helped Toyota become the largest
and one of the most profitable car manufacturers in the world. An excellent and comprehensive presentation of LEAN can be
found in the literature.1,2 LEAN has since been implemented in many manufacturing industries, where it has triggered major transformations. However,
LEAN has often brought only limited benefits. The first reason is that LEAN often has been implemented in a superficial manner,
with a focus on "just-in-time" objectives only, without being understood as an entire system that must permeate an organization's
culture.1 Furthermore, direct applications in the field of biopharmaceutical manufacturing have been quite limited to date because
of concerns about the complexity of the associated technology and stringent regulatory requirements. A few nice examples,
however, have been published recently.3We believe that implementing LEAN the proper way in biopharmaceutical manufacturing can bring huge benefits and help the industry
to deal with increasing pressure on development and manufacturing costs, as well as with challenges in compliance and quality.
In the first part of this article, we present two case studies in which LEAN principles have been applied successfully to
large-scale biopharmaceutical manufacturing, using our radical methodology. In the second part, we describe our qualification
strategy and the implementation of a new flat, process-oriented organization in manufacturing sites, to ensure optimal support
of LEAN and the development of a culture of continuous improvement, as described by the TPS. We conclude with some additional
opportunities for how LEAN can be applied more broadly in (bio)pharmaceutical companies, with great benefits.
OUR LEAN METHODOLOGY
There are many different ways of implementing LEAN across an organization. Our methodology has been shaped over several years
of application in the field of chemical, fill–finish, and now recently biomanufacturing operations. Our approach combines
LEAN and the Six Sigma tools into a unique framework. The benefits of such a combination have been recognized by others.4
1. The first step in our LEAN methodology is a two-day assessment workshop, starting with a simulation game to create a strong
awareness of what can be achieved with LEAN.
2. After defining the exact scope of the project, we assess the efficiency of the corresponding process—typically the manufacturing
step including quality control (QC) and batch release activities—by drawing a high level "value stream map." We use only three
measurements: throughput time, i.e., the overall cycle time for the production and release of a single batch; the throughput
rate, i.e., the number of batches that can be produced per unit of time; and the failure rate, or "right first time" level.
Figure 1
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3. We then set the quantitative objectives of the project, using a radical approach. The team first defines the "blue sky
vision" of the process, i.e., how it would look with none of the current constraints (e.g., regulatory, technological, organizational,
economic, safety-related) (Figure 1). This blue sky vision corresponds to the ideal efficiency level. Then, only the constraints
which cannot realistically be eliminated within the timeframe of the project are carefully added back. This approach leads
to the "practical vision," which determines the LEAN objectives. Experience shows that the practical vision usually remains
a very ambitious target with dramatic improvements compared to the current status (or "baseline"). In a few instances, it
may even be equal to the blue sky vision. This approach has two main advantages over a traditional stepwise optimization process,
where incremental improvements are made sequentially in different areas (e.g., technical, operational, organizational) or
activities (e.g., manufacturing steps). First, with a clear vision of the end-stage, improvements typically are achieved faster
and more dramatically. Second, the mental journey of going first to the ideal and theoretical situation, without claiming
it as possible, turns out to be a very efficient way of circumventing the normal human resistance of team members during the
assessment phase of a LEAN project.
4. In the second day of the workshop, the LEAN implementation plan is developed, systematically including the following key
milestones:
a. selection and implementation of sensitive performance indicators
b. determination of a "drumbeat" for batch production (typically on an hourly basis)
c. overall equipment effectiveness (OEE) improvement at the identified bottleneck (usually the production bioreactor)
d. synchronization of quality assurance (QA) and QC activities with production (thus minimizing waiting time for samples and
accelerating batch record reviews)
e. optimum sequencing of manufacturing activities
f. throughput time reduction through the elimination of non-added value tasks
g. implementation of a new process-oriented organization (see below).
Several different technical tools are used to support LEAN, not only during the assessment workshop, but also during the execution
phase of the project, such as a process walk, value stream mapping, spaghetti diagrams, rhythm wheels, failure mode and effects
analysis (FMEA), and Six Sigma. (A description of these tools is beyond the scope of this article.)
5. A multi-year implementation plan is then built from the above milestones, which typically are translated into specific
sub-projects. Progress during the execution phase is monitored by a steering committee. Short and regular communication to
all the stakeholders and personnel is also very important to support the LEAN transformation of the plant. Visualization of
the LEAN key performance indicators (KPIs) through on-line display on various screens or information boards in the plant is
also usually implemented, so that employees can quickly see and understand the improvements, as suggested by the TPS.
